From coiled coils to small globular proteins: Design of a native‐like three‐helix bundle

Bryson, James W.; Desjarlais, John R.; Handel, Tracy M.; DeGrado, William F.

doi:10.1002/pro.5560070617

Cited by 129 publications

(135 citation statements)

References 85 publications

(71 reference statements)

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“…We simulated four proteins in Protein Data Bank (PDB): α 3 D (PDB ID: 2A3D, 73 residues) (20,21), α 3 W (1LQ7, 67 residues) (22, 23), Fap1-NR α (2KUB, 81 residues) (24) and S-836 (2JUA, 102 residues) (25) in a few microseconds. The first three are parallel three-helix bundles, and the last is a parallel four-helix bundle.…”

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confidence: 99%

Folding helical proteins in explicit solvent using dihedral-biased tempering

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

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Using a single-trajectory-based tempering method with a high-temperature dihedral bias, we repeatedly folded four helical proteins [ α 3 D (PDB ID: 2A3D, 73 residues), α 3 W (1LQ7, 67 residues), Fap1-NR α (2KUB, 81 residues) and S-836 (2JUA, 102 residues)] and some of the mutants in explicit solvent within several microseconds. The lowest root-mean-square deviations of backbone atoms from the experimentally determined structures were 1.9, 1.4, 1.0, and 2.1 Å, respectively. Cluster analyses of folding trajectories showed the native conformation usually occupied the most populated cluster. The simulation protocol can be applied to large-scale simulations of other helical proteins on commonly accessible computing platforms.

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confidence: 99%

Folding helical proteins in explicit solvent using dihedral-biased tempering

Zhang

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…As demonstrated here, metalprotein interactions mediated by such motifs can be strong enough to hold together extensive-and originally repulsiveprotein surfaces that are amenable to structural characterization and subsequent (and iterative) redesign to generate associative interactions. In this regard the utility of crystal structures as a starting point for designing protein structures and interfaces has been well documented (26,27). The most successful de novo interface design efforts to date have focused on coiled-coil motifs with predetermined docking orientations and knowledge-based energy functions (28,29).…”

Section: Discussionmentioning

confidence: 99%

Metal templated design of protein interfaces

Salgado

Ambroggio

Brodin

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

156

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Metal coordination is a key structural and functional component of a large fraction of proteins. Given this dual role we considered the possibility that metal coordination may have played a templating role in the early evolution of protein folds and complexes. We describe here a rational design approach, Metal Templated Interface Redesign (MeTIR), that mimics the time course of a hypothetical evolutionary pathway for the formation of stable protein assemblies through an initial metal coordination event. Using a folded monomeric protein, cytochrome cb 562 , as a building block we show that its non-self-associating surface can be made self-associating through a minimal number of mutations that enable Zn coordination. The protein interfaces in the resulting Zn-directed, D 2 -symmetrical tetramer are subsequently redesigned, yielding unique protein architectures that self-assemble in the presence or absence of metals. Aside from its evolutionary implications, MeTIR provides a route to engineer de novo protein interfaces and metal coordination environments that can be tuned through the extensive noncovalent bonding interactions in these interfaces.evolution | metal coordination | protein self-assembly | protein-protein interactions | templating

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“…10 Other downhill folders that fold downhill even at their T m are either engineered proteins with weaker hydrophobic cores ͑protein Lambda repressor HG͒ 25 or natural proteins with loosely packed hydrophobic cores ͑BBL and gpW͒. 11,23 ␣ 3 D itself has a somewhat lower heat capacity for folding than the average for natural proteins, indicative of slightly greater penetration of water molecules in the native state, 43 and the designed protein was more forgiving of core mutations than for most natural proteins. 44 All of these observations taken together strongly suggest that the reduced desolvation barrier and reduced frustration of less packed hydrophobic cores play important roles in facilitating downhill folding.…”

Section: Discussionmentioning

confidence: 99%

A one-dimensional free energy surface does not account for two-probe folding kinetics of protein α3D

Liu

Dumont

Zhu

et al. 2009

The Journal of Chemical Physics

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We present fluorescence-detected measurements of the temperature-jump relaxation kinetics of the designed three-helix bundle protein ␣ 3 D taken under solvent conditions identical to previous infrared-detected kinetics. The fluorescence-detected rate is similar to the IR-detected rate only at the lowest temperature where we could measure it ͑326 K͒. The fluorescence-detected rate decreases by a factor of 3 over the 326-344 K temperature range, whereas the IR-detected rate remains nearly constant over the same range. To investigate this probe dependence, we tested an extensive set of physically reasonable one-dimensional ͑1D͒ free energy surfaces by Langevin dynamics simulation. The simulations included coordinate-and temperature-dependent roughness, diffusion coefficients, and IR/fluorescence spectroscopic signatures. None of these can reproduce the IR and fluorescence data simultaneously, forcing us to the conclusion that a 1D free energy surface cannot accurately describe the folding of ␣ 3 D. This supports the hypothesis that ␣ 3 D has a multidimensional free energy surface conducive to downhill folding at 326 K, and that it is already an incipient downhill folder with probe-dependent kinetics near its melting point.

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From coiled coils to small globular proteins: Design of a native‐like three‐helix bundle

Cited by 129 publications

References 85 publications

Folding helical proteins in explicit solvent using dihedral-biased tempering

Folding helical proteins in explicit solvent using dihedral-biased tempering

Metal templated design of protein interfaces

A one-dimensional free energy surface does not account for two-probe folding kinetics of protein α3D

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